Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals

Hassan, Mohsin; Moghadamrad, Sheida; Sorribas, Marcel; Muntet, Sergi G.; Kellmann, Philipp; Trentesaux, Chantal; Fraudeau, Marie; Nanni, Paolo; Wolski, Witold; Keller, Irene; Hapfelmeier, Siegfried; Shroyer, Noah F.; Wiest, Reiner; Romagnolo, Béatrice; Gottardi, Andrea De

doi:10.1016/j.jhep.2020.03.019

Cited by 22 publications

(24 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Paneth cells, at the base of the intestinal crypts, synthesise and release antimicrobial peptides that mediate intestinal hostmicrobe interactions. 84,153 In health intestinal macrophages (Mu), in an IL-10 environment, are specialized in the phagocytosis of pathogens that cross the barrier. (Mf) are inert and cannot be activated to secrete inflammatory cytokines.…”

Section: Decompensated Cirrhosis Healthymentioning

confidence: 99%

The multifactorial mechanisms of bacterial infection in decompensated cirrhosis

Merwe

Chokshi

Bernsmeier

et al. 2021

Journal of Hepatology

View full text Add to dashboard Cite

Infections, due to a dysfunctional immune response, pose a great risk to patients with decompensated cirrhosis and herald the beginning of the terminal phase of this disease. Infections typically result from breaches in innate immune barriers and inadequate clearance by immune cells. This leads to bacterial and bacterial product translocation to the systemic circulation, which is already primed by ongoing hepatic inflammation in patients with cirrhosis, who are particularly prone to developing organ failure in the presence of an infection. Early identification of bacterial infection, along with the prompt use of appropriate antibiotics, have reduced the mortality associated with certain infections in patients with decompensated cirrhosis. Judicious use of antibiotic therapy remains imperative given the emergence of multidrug-resistant infections in the cirrhotic population. Important research over the last few years has identified molecular targets on immune cells that may enhance their function, and theoretically prevent infections. Clinical trials are ongoing to delineate the beneficial effects of targeted molecules from their off-target effects. Herein, we review the mechanisms that predispose patients with cirrhosis to bacterial infections, the clinical implications of infections and potential targets for the prevention or treatment of infections in this vulnerable population.

show abstract

Section: Decompensated Cirrhosis Healthymentioning

confidence: 99%

The multifactorial mechanisms of bacterial infection in decompensated cirrhosis

Merwe

Chokshi

Bernsmeier

et al. 2021

Journal of Hepatology

View full text Add to dashboard Cite

show abstract

Section: Small Intestinal Gene Expression Is Altered In the Absence O...mentioning

confidence: 99%

“…However, additional pathways relevant in lymphatic vessel functions including lipid metabolism (GO:0046321) and cell proliferation (GO:0042127) were also affected. Since previous data demonstrated that PCs are involved in the development of the intestinal vasculature [19,21], and biological functions associated to intestinal lymphatics vessels are affected in the mRNA sequencing analysis, we decided to further characterize whether PCs influence the intestinal lymphatic vasculature in the context of portal hypertension. To confirm the results obtained from mRNA sequencing, we investigated whether the depletion of PCs could affect the mRNA expression of genes involved in proliferation and maintenance of lymphatic vessels using RT 2 qPCR array and real-time qPCR (n = 5/group).…”

Section: Small Intestinal Gene Expression Is Altered In the Absence O...mentioning

confidence: 99%

Paneth Cells Regulate Lymphangiogenesis under Control of Microbial Signals during Experimental Portal Hypertension

et al. 2022

Self Cite

View full text Add to dashboard Cite

Intestinal microbiota can modulate portal hypertension through the regulation of the intestinal vasculature. We have recently demonstrated that bacterial antigens activate Paneth cells (PCs) to secrete products that regulate angiogenesis and portal hypertension. In the present work we hypothesized that Paneth cells regulate the development of lymphatic vessels under the control of intestinal microbiota during experimental portal hypertension. We used a mouse model of inducible PCs depletion (Math1Lox/LoxVilCreERT2) and performed partial portal vein ligation (PPVL) to induce portal hypertension. After 14 days, we performed mRNA sequencing and evaluated the expression of specific lymphangiogenic genes in small intestinal tissue. Intestinal and mesenteric lymphatic vessels proliferation was assessed by immunohistochemistry. Intestinal organoids with or without PCs were exposed to pathogen-associated molecular patterns, and conditioned media (CM) was used to stimulate human lymphatic endothelial cells (LECs). The lymphangiogenic activity of stimulated LECs was assessed by tube formation and wound healing assays. Secretome analysis of CM was performed using label-free proteomics quantification methods. Intestinal immune cell infiltration was evaluated by immunohistochemistry. We observed that the intestinal gene expression pattern was altered by the absence of PCs only in portal hypertensive mice. We found a decreased expression of specific lymphangiogenic genes in the absence of PCs during portal hypertension, resulting in a reduced proliferation of intestinal and mesenteric lymphatic vessels as compared to controls. In vitro analyses demonstrated that lymphatic tube formation and endothelial wound healing responses were reduced significantly in LECs treated with CM from organoids without PCs. Secretome analyses of CM revealed that PCs secrete proteins that are involved in lipid metabolism, cell growth and proliferation. Additionally, intestinal macrophages infiltrated the ileal mucosa and submucosa of mice with and without Paneth cells in response to portal hypertension. Our results suggest that intestinal microbiota signals stimulate Paneth cells to secrete factors that modulate the intestinal and mesenteric lymphatic vessels network during experimental portal hypertension.

show abstract

“…Endothelial cells are highly plastic cells that may rapidly switch to an activated state to mediate angiogenesis during wound healing ( 1 , 2 ). Formed blood vessels supply oxygen and nutrients, remove wastes and contribute to the regeneration of various tissues and organs ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

miR‑328a‑3p stimulates endothelial cell migration and tubulogenesis

et al. 2021

View full text Add to dashboard Cite

Endothelial cells have important biological roles after peripheral nerve injury by forming blood vessels within the nerve gap and guiding Schwann cell migration. MicroRNAs (miRNAs/miRs) affect cellular behavior and regulate a wide variety of physiological and pathological activities, including peripheral nerve regeneration. Emerging studies have identified the essential roles of miRNAs in the phenotype modulation of Schwann cells, while the effects of miRNAs on endothelial cells have remained to be thoroughly investigated. miR-328a-3p was differentially expressed in peripheral nerve stumps after nerve injury. In the present study, the effects of miR-328a-3p on biological functions of endothelial cells were determined by transfecting cultured human umbilical vein endothelial cells (HUVECs) with miR-328a-3p mimics or inhibitor. Transfection with miR-328a-3p mimics led to slightly decreased HUVEC proliferation and robustly increased HUVEC migration and tubulogenesis, while transfection with miR-328a-3p inhibitor led to opposite results. Using bioinformatics analysis, potential regulators and effectors of miR-328a-3p were further discovered and a miR-328a-3p-centered competing endogenous RNA network was constructed. Collectively, the present study demonstrated that dysregulated miR-328a-3p after peripheral nerve injury may affect the migration and angiogenesis of endothelial cells and contribute to peripheral nerve regeneration.

show abstract

Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals

Cited by 22 publications

References 45 publications

The multifactorial mechanisms of bacterial infection in decompensated cirrhosis

The multifactorial mechanisms of bacterial infection in decompensated cirrhosis

Paneth Cells Regulate Lymphangiogenesis under Control of Microbial Signals during Experimental Portal Hypertension

miR‑328a‑3p stimulates endothelial cell migration and tubulogenesis

Contact Info

Product

Resources

About